This invention relates to a novel process of producing derivatives of 2,3-dihydro-1,4-dioxino [2,3-f]quinoline in a highly convergent and efficient manner, as well as intermediates thereof. Compounds of the present invention are SSRI/5-HT1A antagonists useful for the treatment of diseases which are caused or affected by disorders of the serotonin-affected neurological systems such as depression, including childhood depression, obsessive compulsive disorders, panic disorder, generalized anxiety disorder, social anxiety disorders, sexual dysfunction, eating disorders such as bulimia, obesity, addictive disorders caused by ethanol or cocaine abuse and dysthymia as described in copending application Ser. No. 60/275,564 filed Mar. 14, 2001.
In accordance with the present invention is provided methods of making compounds of Formula I: 
wherein
R1 is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2, R3, R4, and R6 are, independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms
R5 is hydrogen or alkyl of 1 to 6 carbon atoms;
A dotted line represents an optional double bond;
A and D are selected from carbon, substituted by R1, and nitrogen, provided that at least one of A and D is nitrogen;
E and G are carbon, substituted by R1; and
Z is N or CR6;
or pharmaceutically acceptable salts thereof, comprising the steps of:
a) halogenating a compound of the formula: 
wherein Rxe2x80x2 is alkyl of 1-6 carbon atoms;
with a halogenating reagent to afford a compound of the formula: 
wherein X is Br, Cl, or I;
b) dealkylating the compound of Formula 3 in an acid to afford a compound of the formula: 
c) alkylating the compound of Formula 4 with Rxe2x80x3 protected glycidyl ethers 
wherein Rxe2x80x3 is benzyl or substituted benzyl to afford compound of the formula: 
d) cyclizing the compound of Formula 5 with palladium or copper catalyst to afford a compound of the formula: 
e) debenzylating the compound of Formula 6 to afford the compound of the formula: 
f) activating the hydroxy moiety of the compound of Formula 7 with a sulfonating reagent to afford a compound of the formula: 
wherein Rxe2x80x2xe2x80x3 is an aryl-, or alkyl-sulfonate and
g) coupling the compound of Formula 8 with the appropriate azaheterocycle of Formula 9 
in the presence of base to provide a compound of Formula I.
In alternative embodiments of the present invention the hydroxy moiety of compounds of Formula 7 may be activated to halide to afford a compound of the formula: 
wherein X is I, Br, or Cl and
the compound of Formula 10 may be coupled with the appropriate azaheterocycle of Formula 9 
in the presence of base to provide a compound of Formula I.
In other embodiments of the present invention are provided methods of making compounds of Formula I 
comprising the steps of:
a) halogenating a compound of the formula: 
wherein Rxe2x80x2 is alkyl of 1-6 carbon atoms;
with a halogenating reagent in a solvent to afford a compound of the formula: 
wherein X is Br, Cl, or I;
b) dealkylating the compound of Formula 3 in an acid to afford a compound of the formula: 
c) alkylating the compound of Formula 4 with Rxe2x80x3 protected glycidyl ethers 
wherein Rxe2x80x3 is benzyl or substituted benzyl to afford compound of the formula: 
d) cyclizing the compound of Formula 5 with palladium or copper catalyst to afford a compound of the formula: 
e) debenzylating the compound of Formula 6 to afford the compound of the formula: 
f) activating the hydroxy moiety of the compound of Formula 7 with a sulfonating reagent to afford a compound of the formula: 
wherein Rxe2x80x2xe2x80x3 is an aryl- or alkyl-sulfonate; and
g) coupling the compound of Formula 8 with the appropriate azaheterocycle of Formula 9 
in the presence of base to provide a compound of Formula I.
In alternative embodiments of the present invention the hydroxy moiety of compounds of Formula 7 may be activated to halide to afford a compound of the formula: 
wherein X is I, Br, or Cl and
the compound of Formula 10 may be coupled with the appropriate azaheterocycle of Formula 9 
in the presence of base to provide a compound of Formula I.
In some embodiments of the present invention is provided a method of making a compound of Formula Ia 
comprising the steps:
a) halogenating a compound of the formula: 
wherein Rxe2x80x2 is alkyl of 1-6 carbon atoms;
with a halogenating reagent to afford a compound of the formula: 
wherein X is Br, Cl, or I;
b) dealkylating the compound of Formula 3a in an acid to afford a compound of the formula: 
c) alkylating the compound of Formula 4a with Rxe2x80x3 protected glycidyl ethers 
wherein Rxe2x80x3 is benzyl or substituted benzyl; to afford a compound of the formula: 
d) cyclizing the compound of Formula 5a with palladium or copper catalyst to afford a compound of the formula: 
e) debenzylating the compound of Formula 6a to afford a compound of the formula: 
f) activating the hydroxy moiety of the compound of Formula 7a with a sulfonating reagent to afford a compound of the formula: 
wherein Rxe2x80x2xe2x80x3 is an aryl- or alkyl-sulfonate; and
g) coupling the compound of Formula 8a with 3-tetrahydropyridinyl-indole in the presence of base to provide a compound of Formula Ia.
Alternatively, the hydroxy moiety of compounds of Formula 7a may be activated to halide to afford a compound of Formula 10a 
wherein X is I, Br, or Cl and
the compound of Formula 10a may be coupled with 3-tetrahydropyridinyl-indole in the presence of base to provide a compound of Formula Ia.
In accordance with other aspects of the invention is provided a method of preparing compounds of Formula 5: 
wherein A, D, E, G, X and Rxe2x80x3 are as defined for Formula I and Rxe2x80x3 is benzyl or substituted benzyl, comprising alkylating the compound of Formula 4 
with Rxe2x80x3 protected glycidyl ethers 
wherein Rxe2x80x3 is benzyl or substituted benzyl. In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl, and E and G are unsubstituted carbon.
Further in accordance with the present invention is provided a method of preparing compound of Formula 6 
where A, D, E and G are as defined for Formula I, and Rxe2x80x3 is benzyl or substituted benzyl, comprising the step of cyclizing a compound of Formula 5 
with palladium or copper catalyst. In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl, and E and G are unsubstituted carbon.
Further in accordance with the invention is provided a method of preparing compound of Formula 8 
wherein A, D, E and G are defined as for Formula I and Rxe2x80x2xe2x80x3 is an aryl- or alkyl-sulfonate; comprising activating the hydroxy moiety of the compound of Formula 7 
with a sulfonating reagent. In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl, and E and G are unsubstituted carbon.
Further in accordance with the invention is provided a method of preparing compound of Formula 10 
wherein A, D, E and G are as defined for Formula I, and X is I, Cl or Br, comprising activating compound of Formula 7 
to halide with halophosphorous such as phosphorous triiodide, phosphorous tribromide or phosphorous pentachloride, or with thionyl halide or any standard halogenating reagent.
Further in accordance with the present invention is provided a method of preparing compound of Formula 7 
wherein A, D, E and G are as defined Formula I, comprising debenzylating a compound of Formula 6 
where Rxe2x80x3 is benzyl or substituted benzyl.
In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl and E and G are unsubstituted carbon.
In some embodiments of the invention compound of Formula 2 
is halogenated with a halogenating agent such as N-halosuccinimide wherein halo means bromo-, chloro-, or iodo- in a suitable solvent such as acetonitrile.
In other embodiments of the invention compound of Formula 3 
is demethylated with a Lewis acid in a solvent or a strong protic acid. Preferred Lewis acids include, but are not limited to, boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyl iodine. The preferred solvent is methylene chloride. Strong protic acids include, but are not limited to, HBr and HCl.
Compound of Formula 4 
may be alkylated with Rxe2x80x3 protected glycidyl ethers 
wherein Rxe2x80x3 is benzyl or substituted benzyl in a polar solvent. For instance Rxe2x80x3 may be benzyl, 4-bromobenzyl, 4-chlorobenzyl, 3,4-dimethoxybenzyl, 2- or 4-nitrobenzyl, or 4-methoxyphenyl.
Exemplary polar solvents useful in alkylation of compounds of Formula 4 include dimethylsulfoxide (DMSO), dimethylforamide (DMF), dimethylacetamide (DMA).
Alkylation may be performed in the presence of a base such as, but not limited to, triethylamine, sodium carbonate, or potassium carbonate.
Compound of Formula 5 can be cyclized using palladium catalysts such as, but not limited to, tris(dibenzylideneacetone)dipalladium, tetrakis(triphenyl-phosphine)palladium, or palladium acetate with phosphine ligands including but not limited to (xc2x1) 2,2xe2x80x2-bis(diphenyl-phosphino)-1,1xe2x80x2-binaphthyl (BINAP) and separate enantiomers thereof; (xc2x1) 2,2xe2x80x2-bis(di-p-tolyl-phosphino)-1,1xe2x80x2-binaphthyl (Tol-BINAP) and separate enantiomers thereof; 1-1xe2x80x2-bis(diphenylphosphino)ferrocene; 1,3-bis(diphenylphosphino)propane; and 1,2 bis(diphenylphosphino)ethane in the presence of bases such as sodium hydride (NaH), lithium hydride (LiH), potassium hydride (KH), potassium carbonate, sodium carbonate, titanium carbonate, cesium carbonate, potassium t-butoxide or potassium phosphate tribasic in suitable solvent such as toluene.
Alternatively, compound of Formula 5 can be cyclized with copper catalyst such as copper iodide in the presence of bases such as NaH, LiH, KH in a suitable solvent such as toluene.
Debenzylation of compound of Formula 6 can be carried out with Lewis acids such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyl iodine in a suitable solvent such as methylene chloride.
Debenzylation of compound of Formula 6 may also be carried out with strong protic acids such as HBr and HCl, or alternatively, under reductive cleavage conditions using Pd catalyst and hydrogen transfer reagents such as hydrogen, cyclohexene, methyl cyclohexene, or ammonium formate.
The hydroxy moiety of compound of Formula 7 is activated with a sulfonating reagent such as aryl or alkyl sulfonyl chloride or alkyl or aryl sulfonic anhydride in the presence of a base such as triethylamine or pyridine in suitable solvents such as methylene chloride, tetrahydrofuran (THF), or toluene. Alkyl, as used herein preferably refers to alkyl of 1-6 carbon atom. Aryl, as used herein preferably refers to phenyl. Preferred sulfonating reagents include, but are not limited to p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or 4-nitrobenzenesulfonyl chloride, 2- or 4-bromo-benzenesulfonyl chloride, or trifiluoromethylsulfonic anhydride.
Alternatively the hydroxy moiety of compound of Formula 7 is activated as halogen, such as 1, Br or Cl with reagent such as I3P, Br3P Cl5P or SOCl2 to provide compound of Formula 10.
Compound of Formula 8 or 10 are coupled with azaheterocycles of Formula 9 including 3-tetrahydropyridinyl-indole in the presence of bases such as sodium carbonate, potassium carbonate, or Hxc3xcnig""s base in suitable polar solvents such as THF, dioxane, DMSO, DMF, or DMA to afford compound of Formula I.
Still further in accordance with the present invention are provided novel intermediates of the formula 
wherein:
R7 is hydroxy, alkoxy of 1-6 carbon atoms, or alkoxy of the formula 
wherein R9 is hydroxy, benzyl ether, substituted benzyl ethers such as 4-bromo-benzyl ether, 4-chlorobenzyl ether, 3,4-dimethoxybenzyl ether, 2- or 4-nitrobenzyl ether, or
4-methoxyphenyl; and
R8 is halogen or hydrogen; and salts thereof.
A is nitrogen and D is carbon in preferred intermediates of Formula II.
Also in accordance with the present invention are novel intermediates of the formula 
wherein:
R10 is hydroxy, halide or aryl or alkyl sulfonates; and salts thereof.
A is nitrogen and D is carbon in preferred intermediates of Formula III.
Certain compounds of the present invention contain one asymmetric carbon atom, giving rise to enantiomeric forms of the compounds. It is to be understood that the invention encompasses the enantiomers thereof including racemic mixtures.
It is known that compounds possessing a basic nitrogen can be complexed with many different acids (both protic and non-protic). The invention also includes acceptable salt forms formed from the addition reaction with either inorganic or organic acids. Inorganic acids such as hydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid, phosphoric acid, nitric acid are useful as well as organic acids such as acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, napthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid are useful.
xe2x80x9cHaloxe2x80x9d as used herein, such as in the term xe2x80x9chalosuccinimidexe2x80x9d refers to halogen and preferably bromo-, chloro-, or iodo-.
Thus, in accordance with the present invention is provided a process for preparing in high yield enantiomerically pure compounds of Formula I as well as intermediate thereof.
The process of the present invention can be illustrated by the following reaction scheme (Scheme I), wherein A, D, E, G, Rxe2x80x2, Rxe2x80x3, Rxe2x80x2xe2x80x3, and X are as stated above. The reagents and the solvents for the individual step are given for illustrative purposes only and may be replaced by reagents and solvents known to those skilled in the art. 
This process is characterized by high yields and purity of the products and technical convenience. The synthesis of compound I comprises steps that begin with halogenation of 2 with halogenating reagents such as N-halosuccinimide in acetonitrile to give 3. Deprotecting 3 with Lewis acids such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, or trimethylsilyl iodide in a suitable solvent such as methylene chloride, or with strong protic acids such as HBr and HCl to give the salt of 4. Free base 4 is very water soluble and neutralization is achieved from an Amberlyst A-21 resin slurry in polar solvents such as ethanol or methanol.
Alkylation of 4, either as the free base or as the salt, with benzyl or substituted benzyl protected glycidyl ethers in suitable polar solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), or dimethyl acetamide (DMA) in the presence of bases such as sodium carbonate, potassium carbonate, or triethylamine gives 5.
Compound 5 is cyclized using palladium catalysts such as tris-(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, or palladium acetate with ligands from the group consisting of (xc2x1) 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (BINAP) and separate enantiomers thereof; (xc2x1) 2,2xe2x80x2-bis(di-p-tolylphosphino)-1,1xe2x80x2-binaphthyl (Tol-BINAP) and separate enantiomers thereof; 1-1xe2x80x2-bis(diphenyl-phosphino) ferrocene; 1,3-bis(diphenyl-phosphino)propane; and 1,2-bis(diphenyl-phosphino)ethane in the presence of bases such as NaH, LiH, KH, potassium carbonate, sodium carbonate, titanium carbonate, cesium carbonate, potassium t-butoxide or potassium phosphate tribasic in suitable solvent such as toluene; or alternatively, with copper catalyst such as copper iodide in the presence of bases such NaH, LiH, KH in a suitable solvent such as toluene to afford quinoline 6. Similar dioxanes may also be prepared using the above reagents.
Deprotection of quinoline 6 with Lewis acids such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyl iodide in a suitable solvent such as methylene chloride, or with strong protic acids such as HBr and HCl or under reductive cleavage conditions using Pd catalyst and hydrogen transfer reagents such as hydrogen, cyclohexene, methyl cyclohexene, or ammonium formate to gives 7. The hydroxyl moiety of 7 can be activated with a sulfonating reagent such as an aryl or alkyl sulfonyl chloride or aryl or alkyl sulfonic anhydride such as p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or 4-nitro-benzenesulfonyl chloride, 2- or 4-bromobenzenesulfonyl chloride, or trifluoromethylsulfonic anhydride in the presence of bases such as triethylamine or pyridine in suitable solvents such as methylene chloride, THF, or toluene to afford 8. The final coupling of 8 with azaheterocycle 9, prepared by reaction of indole with the hydrochloride salt of 4-piperidone, in the presence of bases such as Hunig""s base, potassium carbonate, or sodium carbonate in polar solvents such as THF, dioxane, DMSO, DMF, or DMA affords final compound I.
The following examples illustrate the process of the present invention but are not meant to be limiting thereof.